Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2024 Mar;130(5):788-797.
doi: 10.1038/s41416-023-02525-2. Epub 2024 Jan 10.

Phase 1 study of high-dose DFMO, celecoxib, cyclophosphamide and topotecan for patients with relapsed neuroblastoma: a New Approaches to Neuroblastoma Therapy trial

Michael D Hogarty  1   2 , David S Ziegler  3   4   5 , Andrea Franson  6 , Yueh-Yun Chi  7 , Denice Tsao-Wei  8 , Kangning Liu  9 , Rohan Vemu  9 , Eugene W Gerner  10 , Elizabeth Bruckheimer  11 , Anasheh Shamirian  7 , Beth Hasenauer  7 , Frank M Balis  9   12 , Susan Groshen  7 , Murray D Norris  3 , Michelle Haber  3 , Julie R Park  13 , Katherine K Matthay  14 , Araz Marachelian  7
Affiliations
Clinical Trial

Phase 1 study of high-dose DFMO, celecoxib, cyclophosphamide and topotecan for patients with relapsed neuroblastoma: a New Approaches to Neuroblastoma Therapy trial

Michael D Hogarty et al. Br J Cancer. 2024 Mar.

Abstract

Background: MYC genes regulate ornithine decarboxylase (Odc) to increase intratumoral polyamines. We conducted a Phase I trial [NCT02030964] to determine the maximum tolerated dose (MTD) of DFMO, an Odc inhibitor, with celecoxib, cyclophosphamide and topotecan.

Methods: Patients 2-30 years of age with relapsed/refractory high-risk neuroblastoma received oral DFMO at doses up to 9000 mg/m2/day, with celecoxib (500 mg/m2 daily), cyclophosphamide (250 mg/m2/day) and topotecan (0.75 mg/m2/day) IV for 5 days, for up to one year with G-CSF support.

Results: Twenty-four patients (median age, 6.8 years) received 136 courses. Slow platelet recovery with 21-day courses (dose-levels 1 and 2) led to subsequent dose-levels using 28-day courses (dose-levels 2a-4a). There were three course-1 dose-limiting toxicities (DLTs; hematologic; anorexia; transaminases), and 23 serious adverse events (78% fever-related). Five patients (21%) completed 1-year of therapy. Nine stopped for PD, 2 for DLT, 8 by choice. Best overall response included two PR and four MR. Median time-to-progression was 19.8 months, and 3 patients remained progression-free at >4 years without receiving additional therapy. The MTD of DFMO with this regimen was 6750 mg/m2/day.

Conclusion: High-dose DFMO is tolerable when added to chemotherapy in heavily pre-treated patients. A randomized Phase 2 trial of DFMO added to chemoimmunotherapy is ongoing [NCT03794349].

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Swimmers Plot of all patients enrolled (n = 24).
Overall (all responses shown) and component ST, BM and MIBG responses (only CR and PR shown) in enrolled patients, by dose level (dose levels 1–2, 21 day cycles, on left; dose levels 2a-4a, 28 day cycles, on right). CR complete response, CR-MRD complete response-minimal residual disease, MR minor response, PD progressive disease, PR partial response, SD stable disease, ST soft tissue, BM bone marrow, MIBG metaiodobenzylguanethidine detected disease.
Fig. 2
Fig. 2. Kaplan–Meier plots for progression-free survival and overall survival for all patients (n = 24).
At 2 years after starting treatment, PFS probability is 0.295 (95% CI [0.153, 0.566]) and OS probability is 0.583 (95% CI [0.416, 0.818]). For PFS, patients without PD were censored at start of new treatment, or last follow-up if no new treatment. PFS progression-free survival, OS overall survival.
See this image and copyright information in PMC

References

    1. Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D, et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children’s oncology group study. J Clin Oncol. 2009;27:1007–13. - PMC - PubMed
    1. Brodeur GM, Seeger RC, Schwab M, Varmus HE, Bishop JM. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science. 1984;224:1121–4. - PubMed
    1. Seeger RC, Brodeur GM, Sather H, Dalton A, Siegel SE, Wong KY, et al. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. New Engl J Med. 1985;313:1111–6. - PubMed
    1. Fredlund E, Ringner M, Maris JM, Pahlman S. High Myc pathway activity and low stage of neuronal differentiation associate with poor outcome in neuroblastoma. Proc Natl Acad Sci USA. 2008;105:14094–9. - PMC - PubMed
    1. Westermann F, Muth D, Benner A, Bauer T, Henrich KO, Oberthuer A, et al. Distinct transcriptional MYCN/c-MYC activities are associated with spontaneous regression or malignant progression in neuroblastomas. Genome Biol. 2008;9:R150. - PMC - PubMed

Publication types

Associated data